Real-word experience of pazopanib and sorafenib in patients with desmoid tumors: A CanSaRCC multi-center study.

BACKGROUND: Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs. METHODS: Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests. RESULTS: 142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders. CONCLUSION: This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.

Survival Outcomes in Metastatic Ewing Sarcoma Treated With Whole-Lung Radiation.

Background and objective There is a scarcity of research on outcomes in patients with metastatic Ewing sarcoma limited to pulmonary metastases who receive whole-lung radiotherapy (WLRT). In light of this, this study aimed to evaluate the use of WLRT and compare the survival outcomes between patients with metastatic Ewing sarcoma who received treatment with WLRT and those who did not. Materials and methods Patients of all ages with metastatic Ewing sarcoma restricted to the lung who were referred to the British Columbia (BC) Cancer from 1995 to 2017 were identified from the Sarcoma Outcomes Unit (SARCOU). Patient demographics and tumor and treatment characteristics were compared between cohorts treated with WLRT versus those who did not undergo WLRT. Five-year progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier (KM) estimates and compared between treatment groups with log-rank tests. Results The study cohort comprised 30 patients (median follow-up time: 6.8 years). Overall, the median age of the patients was 16 years (range: 4-86 years) and 60% were female; the primary disease sites were as follows: 27% axial skeleton, 53% appendicular skeleton, 20% visceral, 86% had ≥2 lung metastases, and 60% had bilateral disease. Fifteen (50%) patients received WLRT (median of 1500 cGy in 10 fractions). Chemotherapy was used in 97% of patients. The rate of surgery for lung metastases was 40%, which was similar between the WLRT and non-WLRT groups. The median size of the largest lung metastasis in the WLRT cohort was 1 cm (range: 0.3-1.8 cm), compared to 2 cm (range 0.5-6.7 cm) in the non-WLRT cohort (p=0.05). Demographics and tumor characteristics were otherwise not significantly different between the two treatment groups (all p>0.05). Among patients who received WLRT, 53% had complete response (CR), 7% partial response (PR), and 40% had disease progression. The five-year PFS was 86% vs. 59% (p=0.33) and OS was 78% vs. 54% (p=0.24) respectively for patients in the WLRT group vs. those in the non-WLRT group. The five-year PFS outcomes were higher on univariate analysis in patients with appendicular skeletal compared to axial skeletal and visceral primary sites (87.5% vs. 58% vs. 50%, respectively, p=0.02) and in patients with the size of the largest lung metastasis <2 cm vs. those with a size ≥2 cm (80% vs. 25%, p=0.04). Conclusions Patients treated with WLRT had a smaller-volume lung disease and over half of the patients who received WLRT had either complete or partial response. Trends of improved PFS and OS at five years were observed among patients who received WLRT compared to the non-WLRT group, but these were not statistically significant.

Locoregional Treatments for Metastatic Gastrointestinal Stromal Tumor in British Columbia: A Retrospective Cohort Study from January 2008 to December 2017.

INTRODUCTION: The role of surgery and non-surgical locoregional treatments (LRT) such as radiation therapy (RT) and local ablation techniques in patients with metastatic gastrointestinal stromal tumor (GIST) is unclear. This study examines LRT practice patterns in metastatic GIST and their clinical outcomes in British Columbia (BC). METHODS: Patients diagnosed with either recurrent or de novo metastatic GIST from January 2008 to December 2017 were identified. Clinical characteristics and outcomes were analyzed in patients who underwent LRT, including surgical resection of the primary tumor or metastectomy, RT, or other local ablative procedures. RESULTS: 127 patients were identified: 52 (41%) had de novo metastasis and 75 (59%) had recurrent metastasis. Median age was 67 (23-90 years), 58.2% were male, primary site was 33.1% stomach, 40.2% small intestine, 11% rectum/pelvis, and 15.7% others. 37 (29.1%) of patients received palliative surgery, the majority of which had either primary tumor removal only (43.3%) or both primary tumor removal and metastectomy (35.1%). A minority of patients underwent metastectomy only (21.6%). A total of 12 (9.5%) patients received palliative RT to metastatic sites only (58.3%) or primary tumors only (41.7%), mostly for symptomatic control (n = 9). A few patients (n = 3) received local ablation for liver metastatic deposits with 1 patient receiving microwave ablation (MWA) and 2 receiving radiofrequency ablation (RFA). Most patients (n = 120, 94.5%) received some type of systemic treatment. It is notable that prolonged progression free survival (PFS) was observed for the majority of patients who underwent surgery in the metastatic setting with a median PFS of 20.5 (95% confidence interval (CI): 14.29-40.74) months. In addition, significantly higher median overall survival (mOS) was observed in patients who underwent surgery (97.15 months; 95% CI: 77.7-not reached) and LRT (78.98 months; 95% CI: 65.58-not reached) versus no surgery (45.37 months; 95% CI: 38.7-64.69) and no LRT (45.27 months; 95% CI: 33.25-58.66). Almost all patients (8 out of 9) achieved symptomatic improvement after palliative RT. All 3 patients achieved partial response and 2 out of 3 patients had relatively durable responses of 1 year or more after local ablation. DISCUSSION: This study is among the first to systematically examine the use of various LRT in metastatic GIST management. Integration of LRT with systemic treatments may potentially provide promising durable response and prolonged survival for highly selected metastatic GIST patients with low volume disease, limited progression and otherwise well controlled on systemic treatments. These observations, consistent with others, add to the growing evidence that supports the judicious use of LRT in combination with systemic treatments to further optimize the care of metastatic GIST patients.

Intraoperative seed placement for thoracic malignancy-A review of technique, indications, and published literature.

PURPOSE: This review examines the role of permanent radioactive seed implantation in thoracic malignancy. This technique can be used intraoperatively to provide additional highly localized radiation therapy in cases where optimal oncologic margins are unattainable or to palliate unresectable disease. METHODS AND MATERIALS: Relevant trials were identified through a systematic literature search using Pubmed. RESULTS: The intraoperative placement of brachytherapy seeds has been described after sublobar resection for non-small-cell lung cancer (NSCLC), where surgical margins are close or microscopically positive and in the presence of macroscopic residual disease. This brachytherapy technique is currently the focus of a randomized prospective trial in the USA in patients unfit for lobectomy for early-stage NSCLC. CONCLUSIONS: This review summarizes the methods of brachytherapy seed placement and the published experience of brachytherapy implants within the thorax, also examining radiation safety and postoperative dosimetry. This technique has the potential to improve local control with optimal sparing of normal tissue owing to its highly conformal radiotherapy delivery.

Local Relapse and Survival Outcomes in Patients with Scalp Sarcoma: A Retrospective Study of 95 Patients Treated in a Provincial Cancer Care Institution Over 25 Years.

Objectives There is limited literature on the optimal treatment of sarcoma arising in the scalp. This study evaluates local relapse (LR) and survival outcomes of patients with scalp sarcoma treated at a provincial cancer care institution. Methods A retrospective review of 95 patients with a primary diagnosis of scalp sarcoma referred from 1990-2015 was completed. Kaplan-Meier statistics were used to estimate LR-free survival (LRFS) and overall survival (OS). Survival curves were compared using log-rank tests. Regression analyses were performed using Cox proportional hazards model. Results The median age at diagnosis was 77 years. The most common histologies were angiosarcoma (27%), undifferentiated pleomorphic sarcoma (24%), and pleomorphic dermal sarcoma (21%). Final margins were 36% positive, 28% close, 31% negative, and 5% unknown. Of 73 patients treated with curative-intent, 32 (44%) experienced LR. Five-year LRFS was 56.0% and overall survival was 48.3%. Patients with close or positive margins who received pre- or post-operative radiotherapy (n=19) had similar LR risk compared to patients who did not (n=34) (five-year LRFS 41.8% vs 69.1%; p=0.145). On multivariate analysis, angiosarcoma was associated with a higher LR risk (Hazard ratio (HR) 12.06, p<0.001). The use of radiotherapy showed a trend towards reduced LR risk but did not reach statistical significance (HR 0.37, p=0.066). Conclusions Patients with scalp sarcoma have high risk of LR, particularly in cases with positive margins. Adjuvant radiation was not associated with improved local control for close or positive margins. Complete surgical excision to establish negative margins remains the primary standard treatment for patients with this rare disease.

Patterns of Practice Survey: Radiotherapy for Soft Tissue Sarcoma of the Extremities.

Background Neoadjuvant or adjuvant radiotherapy (RT) for extremity soft tissue sarcoma (STS) confers significant local control benefit. To determine patterns of practice, a survey of RT planning practices was undertaken. Method Members of the Connective Tissue Oncology Society and Canadian Association of Radiation Oncology participated in this survey pertaining to general practice patterns of RT for extremity STS, patterns of contouring and planning, and use of quality control measures such as guidelines, tumor boards, and quality assurance rounds. Results A total of 58 radiation oncologists treating extremity STS from 12 countries responded. 89.7% work in academically affiliated centres, and 55.2% saw at least 20 cases of extremity STS per year. Most (96.7%) had access to multidisciplinary sarcoma boards (85.5% of those discussed every referred sarcoma case). 78.6% held quality assurance rounds. Most (92.9%) used planning guidelines. Pre-operative RT was used nearly twice as much as post-operative RT. CT simulation with MR fusion was used by 94.6%. Patterns of clinical target volume (CTV) contouring for both superficial and deep STS were variable. 69.8% contoured a normal soft tissue strip for extremity sarcoma, 13.5% without routine constraints and the remainder with various constraints. Most (91.1%) used 50 Gy in 25 fractions pre-operatively and 39.6% reported using post-operative RT boost for positive margins. Post-operative dose was more variable from 59.4 Gy to 70 Gy. Conclusion Major aspects of RT planning for extremity STS were similar among the responders, and most were academically affiliated. Over twice as many employed pre-operative as opposed to post-operative RT. There was considerable heterogeneity in use of: margins for contouring, normal soft tissue strip as an avoidance structure, and boost for positive margins. This survey shows variable patterns of practice and identifies areas that may require further research.

Permanent planar iodine-125 implants: the dosimetric effect of geometric parameters for idealized source configurations.

PURPOSE: To provide dosimetric information about permanent planar (125)I implants in a manner that is useful to the brachytherapist in the operative setting. METHODS AND MATERIALS: Reference planar permanent implants were simulated for a variety of areas with sources placed uniformly on a 1-cm grid. Implants having variable source spacing and curvature were simulated and compared with the reference implants. Dosimetric measures were calculated at 0.5 and 1.0 cm from the implant plane. RESULTS: A method for calculating dosimetric statistics for permanent implants ranging from 5 x 5 cm to 13 x 13 cm is presented. A formula to predict the reference source strength needed to achieve a desired dosimetric quantity is also presented. The effect of adjusting strand spacing to compensate for source activity is presented and is shown to be an effective means to adjust implants to use source strengths other than the reference strength. The effect of implant curvature compared with flat implants on dosimetric statistics is presented as a function of radius of curvature. CONCLUSIONS: The results presented in this work may be used to provide information about dose delivered from planar permanent implants.

Stage IIIC Endometrial Cancer: Relapse and Survival Outcomes in Women Treated With Pelvic or Extended Field Para-Aortic Nodal Radiation Therapy.

PURPOSE: The optimal radiation (RT) volume for node-positive endometrial cancer is controversial. This study evaluates clinical outcomes in patients with stage IIIC, N1 endometrial cancer who received RT to the pelvis (PV RT) or pelvis plus para-aortic nodes (PV-PAN RT). METHODS: Overall, there were 89 women with stage IIIC endometrial cancer. Of these, 57 women had N1-only disease, forming the study cohort. Clinicopathologic characteristics, recurrence rates, endometrial cancer-specific survival (ECSS), and overall survival (OS) were examined among patients treated with pelvic RT (n=23) compared with pelvic plus para-aortic RT (n=34). Multivariable analysis of ECSS and OS was performed using Cox regression modeling. RESULTS: Median follow-up was 5.1 years. Adjuvant chemotherapy was used in 51/57 (89%) of N1 cases. Women with N1 disease who received PV-PAN RT compared with PV RT experienced lower recurrence (26% vs. 52%, P=0.06) and higher survival rates (5 y ECSS 81.5% vs. 47.0%, P=0.04 and OS 79.1% vs. 47.0%, P=0.01). On multivariable analysis, RT volume was not significantly associated with OS, whereas chemotherapy was associated with improved ECSS and OS. CONCLUSIONS: RT conferred excellent local control, whereas chemotherapy was associated with improved survival in women with N1 endometrial cancer. Distant relapse remains the most common site of recurrence despite chemotherapy.

Magnetic resonance-guided interstitial therapy for vaginal recurrence of endometrial cancer.

PURPOSE: To evaluate the feasibility and to describe the acute toxicity of a real-time intraoperative magnetic resonance (MR)-image guided interstitial approach to treating vaginal recurrence of endometrial cancer. METHODS AND MATERIALS: From February 2004 to April 2005, 10 patients with recurrent endometrial cancer underwent MR-guided interstitial brachytherapy. Parameters evaluated included needle placement, dose-volume histograms (DVH), and complications. RESULTS: Magnetic resonance-image guidance resulted in accurate needle placement. Tumor DVH values included median volume, 47 cc; V100, 89%; V150, 61%; V200, 38%; D90, 71 Gy; and D100, 60 Gy. DVH of organs at risk resulted in a median D2cc of external beam and brachytherapy dose (% of brachytherapy prescription): bladder, 75Gy(3) (88%); rectum, 70Gy(3) (87%); and sigmoid, 56Gy(3) (41%). All patients experienced either a Grade 1 or 2 acute toxicity related to the radiation; only 1 patient had Grade 3 toxicity. No toxicities were attributable to the use of MR guidance. CONCLUSIONS: Real-time MR guidance during the insertion of interstitial needles reduces the likelihood of an inadvertent insertion of the needles into the bladder and the rectum. Three-dimensional dosimetry allows estimation of the dose to organs at risk. Toxicities are limited.

Results of a phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET/CT imaging with induction chemotherapy for patients with non-small cell lung cancer.

Intensity modulated radiation therapy (IMRT) guided by PET/CT imaging with respiratory gating was employed to dose escalate in patients with non-small cell lung cancer (NSCLC), using accelerated fractionation with induction chemotherapies. One patient developed a grade 5 pneumonitis and the study was halted at 84 Gy in 35 fractions.

American Brachytherapy Society (ABS) consensus statement for sarcoma brachytherapy.

PURPOSE: To present recommendations for the use of brachytherapy (BT) in patients with soft tissue sarcoma (STS). METHODS: A group of practitioners with expertise and experience in sarcoma BT formulated recommendations for BT in STS based on clinical experience and literature review. RESULTS: The indications for adjuvant BT are discussed. There is no consensus on the use of BT alone or in combination with external beam radiation therapy (EBRT), but factors that influence the selection of this modality include tumor grade and size, prior surgeries, and tumor recurrence. Low-dose-rate, high-dose-rate, and pulsed-dose-rate radiation are all acceptable BT modalities to use for STS. Recommendations are made for patient selection, techniques, dose rates, and dosages. Outcome data and toxicity data are reviewed. CONCLUSIONS: BT is a useful component of the treatment of STS. The advantages of BT are the targeted dose distribution, low integral dose, and short treatment times. Ultimately the clinician should select the modality or combination of modalities that are most familiar to the treatment team and suitable to the patient.

Should the organs at risk be contoured in vaginal cuff brachytherapy?

PURPOSE: To assess the dose to the organs at risk (OARs) and utility of repeated OAR dose-volume histogram calculations in multifraction high-dose-rate vaginal cylinder brachytherapy using 3-dimensional imaging. METHODS AND MATERIALS: Thirty-eight patients (125 fractions) received high-dose-rate brachytherapy to the vaginal vault between January 2005 and October 2005. All patients emptied their bladders before insertion. After each insertion, a CT scan with 2.5-mm slices and contours of the bladder, rectum, and sigmoid was performed. Dose-volume histograms were generated for the D(0.1cc) and D(2cc) for the OAR using a software program created at our institution. Variance component models estimated the within-patient variance of the dose to the OAR between fractions. Predictors of dose to the OAR were identified using linear mixed models. RESULTS: The within-patient coefficients of variation of total D(0.1cc) dose were bladder 14.0%, rectum 7.9%, and sigmoid 27.6%; for D(2cc), these were 8.1%, 5.9%, and 20.3%, respectively. Intraclass correlations ranged from 0.27 to 0.79. Larger OAR predicted greater total D(0.1cc) and D(2cc). Other predictors of total D(0.1cc) and D(2cc) dose included the size of the cylinder and the length of the treatment field for rectum. CONCLUSIONS: CT simulation provides a noninvasive assessment of the dose to the bladder, rectum, and sigmoid. The small within-patient variation in doses to the bladder and rectum do not support reporting doses to the OARs beyond the initial fraction.

Hypofractionation should be the new 'standard' for radiation therapy after breast conserving surgery.

Hypofractionated whole breast radiation therapy following breast conserving surgery (BCS) has been used in many institutions for several decades. Four randomized trials with 5-10-year follow-up, have demonstrated equivalent local control, cosmetic and normal tissue outcomes between 50 Gy in 25 fractions and various hypofractionated RT prescriptions employing 13-16 fractions. Indirect evidence suggests that hypofractionated RT may also be safe and effective for regional nodal RT. In the face of equivalent outcomes, patient convenience and health care utilization benefits, hypofractionated RT should be the new 'standard' following BCS.

Sigmoid dose using 3D imaging in cervical-cancer brachytherapy.

BACKGROUND AND PURPOSE: To evaluate the proximity, variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning. MATERIALS AND METHODS: Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1 cc and the D2 cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed. RESULTS: The median sigmoid EQD2 D0.1 cc and D2 cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p=0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1-6.16 cm) for HDR and 2.7 cm (rg, 1.17-4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were -0.1 cm (rg, -1.4 to 2.5 cm) and 0.44 cm (rg. -0.73-5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p<0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation =40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period. CONCLUSIONS: 3D imaging in cervical-cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid-to-tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction.

Synovial cell sarcoma of the vulva: multimodality treatment incorporating preoperative external-beam radiation, hemivulvectomy, flap reconstruction, interstitial brachytherapy, and chemotherapy.

BACKGROUND: Vulvar synovial cell sarcomas are rare, with only four previously published cases in the literature. Traditionally, the primary management for these tumors has been surgery alone. CASE: We report a case of a large vulvar synovial cell sarcoma in a 50-year-old woman treated with comprehensive combined multimodality management, including preoperative intensity-modulated radiation therapy, radical hemivulvectomy, flap reconstruction, interstitial low-dose-rate brachytherapy boost, and adjuvant chemotherapy. CONCLUSION: Based on this case and the limited data in the literature, multimodality treatment of advanced soft tissue sarcoma of the vulva may optimize local control and minimize toxicity while preserving sexual function.

Cutaneous angiosarcoma of the scalp: a case report of sustained complete response following liposomal Doxorubicin and radiation therapy.

Cutaneous angiosarcomas of the head and neck are aggressive cancers with a mean overall survival of 30 months. We add to the literature a case report of a 65-year-old man with a large, >10 cm, unresectable, angiosarcoma of the scalp who was treated with two cycles of liposomal doxorubicin (Caelyx(R)) followed by electron beam radiation therapy (30 Gy in 10 fractions over 2 weeks) who has sustained a complete response with a 4-year follow-up. The dose and fractionation of the radiation therapy in this case was palliative and was not expected to give lasting local control of this lesion. It is therefore possible that either the genetic profile of the tumour conferred radiosensitivity or that the radiation therapy induced a recall phenomenon of the liposomal doxorubicin.

Role of exercise and lung function in predicting work status in cystic fibrosis.

With larger numbers of adult patients with cystic fibrosis (CF) in the workplace, the issue of disability has arisen increasingly. We examined relationships between measures of pulmonary impairment and work/school capability and then determined whether quantification of aerobic fitness improved predictability of disease-related disability. We studied 73 patients with CF who performed lung function and exercise capacity tests, completed a work/education questionnaire, and were scored for clinical and chest radiographic status. Patients who were characterized as unemployed and in poor health had more severe pulmonary disease according to American Thoracic Society impairment/disability criteria. Subjects were further classified into three groups based on employment or education status over the preceding 12 months. FEV1, maximal oxygen consumption, Schwachman-Kulczycki clinical and Brasfield radiographic scores, and frequency of pulmonary exacerbations over 2 years were associated with disability, but change in FEV1 over 2 years and oxygen saturation at rest or exertion were not. FEV1 and Schwachman-Kulczycki scores were the best independent predictors of impairment/disability; specific thresholds used in other pulmonary diseases were of limited utility. We conclude that after accounting for either current level of FEV1 or Schwachman-Kulczycki scores, no other physiological or clinical measures contribute to predicting limitation in a work or school environment.